The T cell repertoire is generated through a tightly regulated developmental program of selection or “filtering” in which thymocytes bearing immunologically desirable T cell receptor (TCR) specificities are preserved and those expressing harmful specificities are eliminated (reviewed in Fowlkes and Pardoll, Adv. Immunol. 44:207–264 (1989)). T-lineage cells expressing autoreactive TCRs are deleted in the thymus via a process termed negative selection (reviewed in Nossal, Cell 76:229–239 (1994)). Multiple lines of evidence utilizing both normal and transgenic mice show that this negative selection process occurs during a restricted stage(s) of thymic differentiation (Fowlkes and Pardoll, Adv. Immunol. 44:207–264 (1989); Fowlkes et al., Nature 334:620–623 (1988); Kisielow et al., Nature 333:742–746 (1988); Murphy et al., Science 250:1720–1723 (1990); Vasquez et al., J. Exp. Med. 175:1307–1316 (1992); Sebzda et al., Science 263:1615–1618 (1994)). The deletion process requires TCR recognition of antigenic peptides displayed on antigen presenting cells in complex with major histocompatibility complex (MHC) class I or class II molecules, and generally involves thymocytes at the double positive (DP) stage of development.
Although the mechanism of negative selection is unknown, the targeted thymocytes die via apoptosis (Murphy et al., Science 250:1720–1723 (1990)), a physiologically controlled form of cell death utilized by metazoan organisms during normal development, as well as for homeostasis (reviewed in Steller, Science 267:1445–1449 (1995); Vaux, Proc. Natl. Acad. Sci. USA 90:86–789 (1993); Vaux and Strasser, Proc. Natl. Acad. Sci. USA 93:2239–2244 (1996)). Apoptosis occurs as a consequence of extracellular signalling events such as crosslinking of certain receptors, including CD95 (Trauth et al., Science 245:301–305 (1989); Yonehara et al., J. Exp. Med. 169:1747–1756 (1988); Itoh and Nagata, J. Biol. Chem. 268:10932–10937 (1993); Alderson et al., Intl. Immunol. 6:1799–1806 (1994); Takahashi et al., Cell 76:969–976 (1994)), TNF receptors (Tartaglia et al., Cell 74:845–853 (1993)) and a recently identified Death Receptor 3 (DR3) (Chinnaiyan et al., Science 274:990–992 (1996a)) or as a result of growth factor withdrawal (reviewed in Yang and Korsmeyer, Blood 88:386–401 (1996)). Upon induction of apoptosis, cells undergo a morphologically characteristic process of nuclear condensation, blebbing of cellular membranes and disintegration into small fragments which are removed by phagocytes (reviewed in Steller, Science 267:1445–1449 (1995); Vaux, Proc. Natl. Acad. Sci. USA 90:86–789 (1993); Vaux and Strasser, Proc. Natl. Acad. Sci. USA 93:2239–2244 (1996)).